Urinary tract infections (UTIs) are the second most common infectious disease that accounts for 8-11 million physicians' visits annually in the United States and costs ~$4 billion in healthcare expense. One in three of those who have had a UTI will go on to experience multiple episodes. No effective therapeutic regimen exists for these recurrent UTIs. Recent studies indicate that a pivotal step for uropathogenic E. coli (UPEC), the most prevalent pathogen, to cause the UTIs is for the bacterium to adhere to and invade the bladder epithelial cells. Once adherent to or invading into the urothelial cells, UPEC can trigger divergent urothelial responses including programmed cell death as a defense to shed UPEC-laden urothelial cells or cell survival to become short- and long-term bacterial hosts. Despite these recent advances, many key questions remain. What is the urothelial surface receptor for UPEC in vivo that allows bacterial attachment? How does UPEC binding to urothelial surface trigger signal transduction that leads to UPEC invasion? Precisely why does UPEC infection result in urothelial apoptosis and survival, two diametrically opposing biological events? To address these questions, we will employ a series of well-defined, genetically engineered mouse models. In Aim One, we will provide in vivo evidence to verify whether uroplakin la, a principal mannosylated glycoprotein of the mammalian urothelial surface, serves as the urothelial receptor for type i-fimbriated E. coli and that deficiency or loss of high mannose glycosylation of uroplakin la in vivo will reduce bladder infection of the mutant mice by UPECs. In Aim Two, we will test the hypothesis that uroplakin Illa and Illb, major and minor component, respectively, of the urothelial surface play crucial roles in transducing transmembrane signals important for UPEC invasion. In Aim Three, we will test the hypothesis that the functional status of NF-kB, a key integrator of host responses to bacterial infections, both spatially and temporally, determines whether urothelial cells undergo apoptosis or survive to become bacterial hosts. Together, these studies should yield insights into the intricate interplay between UPEC and host urothelial cells and provide clues for rational design of novel approaches to better treat and prevent UTIs.